Constitutional Aberrations Research Articles

Spectrum of hematological malignancies, clonal evolution and outcomes in 144 Mayo Clinic patients with germline predisposition syndromes.

Germline predisposition syndromes (GPS) result from constitutional aberrations in tumor suppressive and homeostatic genes, increasing risk for neoplasia in affected kindred. In this study, we present clinical and genomic data on 144 Mayo Clinic patients with GPS; 59 evaluated prospectively using an algorithm-based diagnostic approach in the setting of a dedicated GPS/ inherited bone marrow failure syndrome (IBMFS) clinic. Seventy-two (50%) patients had IBMFS (telomere biology disorders-32,Fanconi anemia-18, Diamond Blackfan Anemia - 11, congenital neutropenia-5, Schwachman-Diamond Syndrome-5 and Bloom Syndrome-1), 27 (19%) had GPS with antecedent thrombocytopenia (RUNX1-FPD-15, ANKRD26-6, ETV6-2, GATA1-1, MPL-3), 28 (19%) had GPS without antecedent thrombocytopenia (GATA2 haploinsufficiency-16, DDX41-10, CBL-1 and CEBPA-1) and 17 (12%) had general cancer predisposition syndromes (ataxia telangiectasia-7, heterozygous ATM variants-3, CHEK2-2, TP53-2, CDK2NA-1, NF1-1 and Nijmegen Breakage Syndrome-1). Homozygous and heterozygous ATM pathogenic variants were exclusively associated with lymphoproliferative disorders (LPD), while DDX41 GPS was associated with LPD and myeloid neoplasms. The use of somatic NGS-testing identified clonal evolution in GPS patients, with ASXL1, RAS pathway genes, SRSF2 and TET2 being most frequently mutated. Fifty-two (91%) of 59 prospectively identified GPS patients had a change in their management approach, including additional GPS-related screening in 42 (71%), referral for allogenic HSCT workup and screening of related donors in 16 (27%), medication initiation and selection of specific conditioning regimens in 14 (24%), and genetic counseling with specific intent of fertility preservation and preconceptual counseling in 10 (17%) patients; highlighting the importance of dedicated GPS screening, detection and management programs for patients with hematological neoplasms.

Patterns and frequencies of acquired and constitutional uniparental isodisomies in pediatric and adult B-cell precursor acute lymphoblastic leukemia.

Single nucleotide polymorphism (SNP) arrays are increasingly being used in clinical routine for genetic analysis of pediatric B-cell precursor acute lymphoblastic leukemias (BCP ALL). Because constitutional DNA is not readily available as a control at the time of diagnosis, it is important to be able to distinguish between acquired and constitutional aberrations in a diagnostic setting. In the present study we focused on uniparental isodisomies (UPIDs). SNP array analyses of 143 pediatric and 38 adult B-cell precursor acute lymphoblastic leukemias and matched remission samples revealed acquired whole chromosome or segmental UPIDs (wUPIDs, sUPIDs) in 32 cases (18%), without any age- or gender-related frequency differences. Acquired sUPIDs were larger than the constitutional ones (mean 35.3 Mb vs. 10.7 Mb; P < 0.0001) and were more often terminally located in the chromosomes (69% vs. 4.5%; P < 0.0001). Chromosomes 3, 5, and 9 were most often involved in acquired wUPIDs, whilst recurrent acquired sUPIDs targeted 6p, 9p, 9q, and 14q. The majority (56%) of sUPID9p was associated with homozygous CDKN2A deletions. In pediatric ALL, all wUPIDs were found in high hyperdiploid (51-67 chromosomes) cases and an extended analysis, also including unmatched diagnostic samples, revealed a higher frequency of wUPID-positivity in higher modal number (56-67 chromosomes) than in lower modal number (51-55 chromosomes) high hyperdiploid cases (34% vs. 11%; P = 0.04), suggesting different underlying mechanisms of formation of these subtypes of high hyperdiploidy. © 2016 Wiley Periodicals, Inc.

Evidence of an Epigenetic Origin for High-Risk 1q21 Copy Number Aberrations in Multiple Myeloma

Multiple myeloma (MM) is a B-cell malignancy stratified in part by cytogenetic aberrations including the high-risk copy number alterations (CNAs) of 17p- and +1q21. CNAs of 1q21 are known to occur as a result of jumping translocations of 1q (JT1q12) which increase the copy number (CN) of 1q21, while at the same time causing collateral genomic damage including deletions and amplifications in some receptor chromosomes (RC). We have previously reported the decondensation of the 1q12 region and triradial chromosomes in the bone marrow specimens of patients with aggressive disease, and have speculated that hypomethylation of the pericentromeric region of 1q12 may play a role in the origin of 1q21 CNAs. To test the hypothesis that 1q12 hypomethylation induces CN gains of 1q21, we used the hypomethylating agent 5-azacytidine to treat blood lymphocyte cultures of five myeloma patients with balanced constitutional 1q12 aberrations as well as five normal control subjects. The patients with constitutional aberrations of 1q12 were selected based on their potential to show either novel CN gains of regions translocated distal to 1q12 or CN gains of 1q21 when 1q12 was translocated to a non-homologous chromosome. The constitutional aberrations included two patients with pericentromeric inversions of chromosome 1 inv(1)(p11q12), and one patient each with a balanced translocation of t(1;2)(q12;p11), t(1;2)(q12;q34), or t(1;9)(q12;q11). These particular aberrations should provide a unique model for testing the association between the hypomethylation of 1q12 and the origin of CN gains of 1q21. In vitro blood lymphocyte cultures of patients and controls were treated for 72 hours with 5-azacytidine at a final concentration of 10uM. 5-azacytidine is known to cause site-specific hypomethylation and chromatin decondensation in the 1q12 region. Utilizing FISH probes for 1q12 (satII/III) and 1q21(CKS1B), we analyzed 100 metaphase cells from each patient and each control for CN gains for 1q21 and any novel region translocated distal to 1q12. To fully characterize the induced rearrangements of 1q12, we also applied inverse G-banding and spectral karyotyping in selected cells. Remarkably, all patients with the balanced constitutional 1q12 rearrangements showed CN gains of chromosome regions on the derivative chromosomes distal to the inverted or translocated 1q12 regions. Recurring aberrations of 1q12 included pericentromeric decondensation and triradials of chromosome arms 1q, 1p, and 2p, in addition to localized pulverizations distal to 1q12 of these same arms. Specifically, in both patients with inv(1), whole-arm CN gains of 1p were identified in 2-3% of cells, while in the patient with t(1;2)(q12;p11), whole-arm gains of 2p (MYCN) were identified in 3% of cells. In these same three patients, on the derivative chromosomes where the 1q12 region was separated from 1q21 by an inversion or translocation, no CN gains of the 1q21 occurred. In the patients with 1q12 translocated to a non-homologous chromosome, 1q21 was amplified on the RC in 4% of the cells in the patient with t(1;2)(q12;q34), and in 3% in the patient with t(1;9)(q12;q11). Control subjects showed CN gains of 1q21on both chromosomes 1 in the range of 3-13%. Whole-arm JT1q12s to RC16q were identified in three patients and three controls. This JT1q12 results in a CN gain of 1q21, and a whole-arm CN loss in RC16q, identical to those found in the bone marrow specimens of MM patients. Interestingly, one control showed JT1q12s to two different RCs, 9q and 12q, causing whole-arm deletions in the long arms of both. The key structural aberration responsible for the generation of CN gains of 1q21 and subsequent JT1q12s is the formation of a triradial involving the 1q12 region. The novel finding in this study is the induction of triradials and CN gains for chromosome arms of 1p and 2p, which demonstrates that epigenetic modifications to 1q12 can amplify non-homologous chromosome regions juxtaposed to it. Furthermore, the CN gains induced here occurred only distal to 1q12 on all normal and derivative chromosomes and mimic the triradials and JT1q12s reported in the bone marrow of patients with aggressive disease. These findings demonstrate for the first time that the hypomethylation of the 1q12 region can potentially amplify any genomic region distal to it, and provide evidence for an epigenetic origin of the high-risk 1q21 CNAs found in the progression of MM. DisclosuresNo relevant conflicts of interest to declare.

On the significance of germline cytogenetic rearrangements at MYCN locus in neuroblastoma

BackgroundMYCN oncogene amplification is the most important prognostic factor in neuroblastoma. 25% neuroblastoma tumors have somatic amplifications at this locus but little is known about its constitutional aberrations and their potential role in carcinogenesis. Here, we have performed an array-CGH and qPCR characterization of two patients with constitutional partial 2p trisomy including MYCN genomic region.ResultsOne of the patients had congenital neuroblastoma and showed presence of minute areas of gains and losses within the common fragile site FRA2C at 2p24 encompassing MYCN. The link between 2p24 germline rearrangements and neuroblastoma development was reassessed by reviewing similar cases in the literature.ConclusionsIt appears that constitutional rearrangements involving chromosome 2p24 may play role in NB development.

Defects in the DNA Mismatch Repair System Do Not Contribute to the Development of Childhood Wilms Tumors

Wilms tumor is the most common childhood renal malignancy. Most Wilms tumors occur sporadically, whereas a genetic predisposition is described in 9-19% of the Wilms tumor patients. In addition to constitutional aberrations, somatic aberrations in multiple genetic loci such as WT1, WT2 or locus 11p15.5, CTNNB1, WTX, TP53, FBXW7, and MYCN have also been linked to Wilms tumorigenesis. In sporadic Wilms tumors, however, the driving somatic genetic aberrations need to be further unraveled. Therefore, it is necessary to obtain more insight into other underlying mechanisms. Little is known about the role of defects in the DNA mismatch repair system in the etiology of Wilms tumors. To detect mismatch repair deficiency in a full cohort of Wilms tumor patients, we combined immunohistochemistry for the expression of mismatch repair proteins and microsatellite instability (MSI) analysis by a fluorescent multiplex polymerase chain reaction-based assay. Of the 121 Wilms tumor patients treated between 1987 and 2010 in our institution, 100 samples from 97 patients were available for analysis. Nuclear staining for MLH1, MSH2, MSH6, and PMS2 proteins was present in all 100 Wilms tumor samples. No pattern of MSI was found in any of the 100 investigated Wilms tumor samples. The matching results of normal expression of the mismatch repair proteins detected by immunohistochemistry and the absence of MSI by DNA analysis in 100 Wilms tumor samples lead us to conclude that defects in the DNA mismatch repair system do not play a significant role in the development of Wilms tumors.

Frequency of WT1 and 11p15 constitutional aberrations and phenotypic correlation in childhood Wilms tumour patients

IntroductionIn 9–17% of Wilms tumour patients a predisposing syndrome is present, in particular WT1-associated syndromes and overgrowth syndromes. Constitutional WT1 mutations or epigenetic changes on chromosome 11p15 have also been described in Wilms tumour patients without phenotypic abnormalities. Thus, the absence of phenotypic abnormalities does not exclude the presence of a genetic predisposition, suggesting that more Wilms tumour patients may have a constitutional abnormality. Therefore, we investigated the frequency of constitutional aberrations in combination with phenotype. Patients & methodsClinical genetic assessment, as well as molecular analysis of WT1 and locus 11p15 was offered to a single-centre cohort of 109 childhood Wilms tumour patients. ResultsTwelve patients (11%) had a WT1 aberration and eight patients (8%) had an 11p15 aberration. Of the 12 patients with a WT1 aberration, four had WAGR syndrome (Wilms tumor, aniridia, genitourinary malformations and mental retardation), one had Denys-Drash syndrome, four had genitourinary anomalies without other syndromic features and three had bilateral disease with stromal-predominant histology at young age without congenital anomalies. Of the eight patients with an 11p15 aberration, four had Beckwith–Wiedemann syndrome (BWS), two had minor features of BWS and two had no stigmata of BWS or hemihypertrophy. ConclusionConstitutional WT1 or 11p15 aberrations are frequent in Wilms tumour patients and careful clinical assessment can identify the majority of these patients. Therefore, we would recommend offering clinical genetic counselling to all Wilms tumour patients, as well as molecular analysis to patients with clinical signs of a syndrome or with features that may indicate a constitutional WT1 or 11p15 aberration.

‘Reverse Discrimination’ in EU Law: Constitutional Aberration, Constitutional Necessity, or Judicial Choice?

This contribution revisits the phenomenon of ‘reverse discrimination in the light of the latest Treaty amendments, recent developments in the CJEU's case law and evolutions in the law of selected Member States. It follows that ‘reverse discrimination’ caused by national measures applying to internal situations in non-harmonized policy fields remains acceptable under EU law as a matter of principle. The Union's non-unitary constitutional structure compels the CJEU to exercise judicial restraint when reviewing such rules against the fundamental freedoms of the Treaties as long as the Union legislator does not address the issue. Although the CJEU's traditional and increasingly incoherent case-law on ‘purely internal situations’ is not a necessary corollary of this reasoning, alternative judicial approaches risk unduly undermining Member States' competences and constitutional identities. Whilst much of the academic debate on reverse discrimination focuses on possible remedies under EU law, this paper also looks at solutions available under national law. Member States are well equipped to address reverse discrimination and to progressively live up to their responsibility in this respect. Evidence from different Member States suggests that national law (subject to an external control of the ECtHR) can provide a valuable and effective tool to assess whether or not restrictions of individual freedoms can be justified by overriding constitutionally recognized principles.

Acquired pericentric inversion of chromosome 9 in acute myeloid leukemia

Pericentric inversion of chromosome 9 involving the qh region is relatively common as a constitutional genetic aberration without any apparent phenotypic consequences. However, it has not been established as an acquired abnormality in cancer. Among the three patients reported so far in the literature with acquired inv(9), only one had acute myeloid leukemia (AML). Here we describe an unique case where both chromosomes 9 presented with an acquired pericentric inversion with breakpoints at 9p13 and 9q12 respectively, in a AML patient with aberrant CD7 and CD9 positivity. Additionally, one der(9) also showed short arm deletion at 9p21 to the centromeric region and including the p16 gene. The constitutional karyotype was normal. This is probably the first report describing an acquired inv(9) involving both chromosomes 9 in AML. The possible significance of this inversion is discussed.

Interstitial deletion of a proximal 3p: A clinically recognisable syndrome

Interstitial deletions of the proximal short arm of chromosome 3 occurring as constitutional aberrations are rare and a defined clinical phenotype is not established yet. We report on a 30-months-old girl with distinct facial features (square facies, plagiocephaly, broad forehead, broad nasal bridge, long philtrum and low set ears) and psychomotor/speech delay associated with an interstitial deletion of 3p12 chromosomal band, del(3)(p12p12). Clinical manifestations of our child were compared with those of other eight patients with the same deletion previously described to further delineate the proximal 3p deletion syndrome.

Multiple Constitutional Chromosome Translocations of Familial Nature in Philadelphia Chromosome-Positive Chronic Myeloid Leukemia: A Report on a Unique Case

A case of Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia (CML) featuring 2 additional balanced translocations, t(2;5) and t(6;12), as well as a robertsonian translocation, t(13;14), was diagnosed by routine bone marrow karyotyping. The breakpoints did not involve previously described CML-related chromosomal regions in any of the 3 translocations. Despite the patient's partial response following imatinib therapy, all Ph(-) bone marrow metaphases persistently had the 3 additional chromosomal changes. Moreover, stimulated peripheral B-lymphocytes from the patient also showed the same chromosomal changes, suggesting that we had found a complex constitutional chromosome aberration unrelated to the leukemia. Peripheral blood karyotype analyses of 6 of the 7 closest relatives from 3 generations demonstrated at least 1 of these aberrations, although in different combinations. Standard bone marrow or peripheral blood karyotyping of hematologic disorders may uncover otherwise symptomless, unrelated constitutional changes together with disease-specific chromosome aberrations.A triple constitutional chromosome aberration combined with a hematologic disorder has not been described until now. In addition, multiple constitutional aberrations persisting through at least 3 generations seem to be extremely rare. At present, no direct evidence exists to support a causative relationship between the familial translocations and leukemogenesis.

Correlation of age and birth order of parents with chromosomal anomalies in children.

One hundred children with suspected congenital and/or malformation and their parents who reported to SAT hospital, Medical College, Trivandrum, India formed the test group. Fifty children with no obvious anomalies or abnormalities and their parents formed the control group. The criteria for selection of the control was 1) the maternal age at delivery was below 30 years and 2) the parents belong to 1st or 2nd birth order. The chromosomal analysis was carried out in all the subjects using peripheral blood lymphocyte microculture to investigate for any constitutional chromosomal markers and quantitate the mutagen (bleomycin) sensitivity of the chromosomes. All the subjects were evaluated clinically and a complete family history was recorded. Chromosome anomalies were noted in 41 out of the one hundred children and in 4 out of the 200 parents of the test group. No constitutional aberrations were seen either in the parents or in the children of the control group. Bleomycin sensitivity study revealed a high b/c value in 35 children (24 hypersensitive and 11 sensitive) of the test group whereas in the control group the b/c values were low denoting hyposensitivity and very good DNA repair mechanism. This study reveals that the incidence of chromosome aberrations is higher when the age and birth order of parents are higher. A direct correlation was noted with parental order and b/c value. This was also true with the parental age and birth defects.

Chromosomal factors of infertility in candidate couples for ICSI: an equal risk of constitutional aberrations in women and men.

To assess the frequency of chromosomal aberrations in French candidates for intracytoplasmic sperm injection (ICSI), and to explore the existence of a female chromosomal factor in some cases of couple infertility, a collaborative retrospective clinical and cytogenetic study was performed, launched by the Association des Cytogénéticiens de Langue Franciaise (ACLF). The karyotypes of 3208 patients [2196 men (68.4%), 1012 (31.6%) women] included in ICSI programmes over a 3-year period in France were collected. A total of 183 aberrant karyotypes was diagnosed, corresponding to an abnormality frequency of 6.1% (134/2196) for men and 4.84% (49/1012) for women. The following frequencies of abnormalities were observed respectively for men and women: 1.23% (n = 27) and 0.69% (n = 7) for reciprocal translocations, 0.82% (n = 18) and 0.69% (n = 7) for Robertsonian translocations, 0.13% (n = 3) and 0.69% (n = 7) for inversions, 3.32% (n = 73) and 2.77% (n = 28) for numerical sex chromosome aberrations, and 0.59% (n = 13) and 0% for other structural aberrations. Among the male patients of this latter group, 0.40% (n = 9) had a Y chromosome abnormality. Among the male patients with numerical sex chromosome abnormalities, 2.23% (n = 49) were 47,XXY, 0.32% (n = 7) were 47,XYY, and 0.77% (n = 17) had a mosaicism for numerical sex chromosome anomalies. All the female patients with sex chromosome abnormalities (2.77%, n = 28) had mosaicism for numerical sex chromosome anomalies. Even if these cases-the significance of which was sometimes questioned-were disregarded in the analysis, 2.08% (21/1012) of abnormal karyotypes remained in women. An overall increased frequency of chromosomal aberrations was found, and this confirmed that in some cases of poor reproductive outcome there may be a contribution of maternal chromosome aberrations. Indeed, the existence of a chromosome abnormality in the female partner was associated with the group of infertile men in which there was no apparent cause of infertility.

Type and frequency of chromosome aberrations in 781 couples undergoing intracytoplasmic sperm injection.

Cytogenetic investigations were performed in 781 couples prior to intracytoplasmic sperm injection (ICSI) because of severe male infertility or fertilization failures in previous in-vitro fertilization attempts. Out of these 1562 patients, 1012 had a normal karyotype without any aberrations (64.8%), 204 patients had an abnormal karyotypes (13.1%). These chromosome aberrations included constitutional aberrations (4.4%), fragile sites of autosomes (3.0%), low level mosaicism of sex chromosomes (4.0%) and secondary structural chromosome aberrations (4.2%). Combinations of different types of abnormalities were stated. Another 346 patients (22.1%) showed single cell aberrations; the significance of these is unclear at the moment. Constitutional chromosome aberrations were detected in 69 patients. The following chromosome aberrations were observed: 35 sex chromosomal aberrations (comprising hyperploidies of X or Y chromosomes, mosaicisms and derivative X and Y chromosomes), 34 autosomal aberrations including 14 reciprocal translocations, five Robertsonian translocations, six inversions, one marker chromosome, one trisomy 18 mosaicism and seven other structural aberrations. Three autosomal regions showed fragile sites: 6q13 in 2.9% of the patients, 17p12 and 10q24 in 0.05% each. In conclusion, our data show that a high number of infertile couples in an ICSI programme are affected by chromosome aberrations which occur in both sexes. It is suggested that a chromosomal analysis should be performed on both partners before ICSI treatment is initiated.

Wilms tumor genetics.

Wilms tumor (WT), a sporadic and familial childhood kidney tumor, is genetically heterogeneous. One WT gene, WT1 at 11p13, has been cloned, but only a minority of WTs carry detectable mutations at that locus. WT1 can also be excluded as the predisposition gene in most WT families, implying the existence of other WT genes. Studies of WT families have demonstrated that familial predisposition is also heterogeneous and involves at least two other loci besides WT1. In addition to WT1 and the familial predisposition genes, a role for other genes in the development of WTs is implied by the somatic occurrence of genetic and epigenetic alterations such as loss of heterozygosity and loss of imprinting in tumors and, rarely, the observation of nonchromosome-11 constitutional aberrations in WT patients. Determining the pattern of presence or absence of these various genetic alterations in tumors and elucidating the function of the genes involved will provide a better understanding of the cellular processes that are critical for normal cell growth and differentiation, but are abrogated in the course of tumorigenesis.

Detection of a cryptic paracentric inversion within band 11p13 in familial aniridia by fluorescence in situ hybridization.

We report the first familial case of dominantly inherited aniridia with a cryptic inversion within band 11p13. High-resolution chromosome analysis gave a suspicion of a tiny constitutional aberration around band 11p13 and fluorescence in situ hybridization using 11p cosmids successfully confirmed that the aniridia patients of this family have an inversion within band 11p13. The distal breakpoint of the inversion is telomeric to a candidate aniridia gene (AN2) and suggests that more genes might be involved in the etiology of aniridia. In situ hybridization is a powerful tool to detect cryptic rearrangements in sporadic or familial patients with aniridia. This family indicated the importance of careful observation of the 11p13 region of aniridia patients, even if the aniridia was autosomal dominantly inherited.

Cytogenetic survey of 31 patients treated with bone marrow transplantation for acute nonlymphocytic and acute lymphoblastic leukemias

The authors report on a sequential cytogenetic study carried out on 31 patients with acute leukemia (20 with acute lymphoblastic leukemia and 11 with acute non-lymphocytic leukemia) who underwent bone marrow transplantation (BMT). Engraftment was documented in all patients with sex-mismatched donors and with donor constitutional aberrations. During the follow-up, ranging from 6 to 110 months, clinical and hematologic relapse was observed in 11 patients (35.5%). Five of these cases showed a normal karyotype, 3 were of undefined relapse origin, 2 were aneuploid karyotypes, and one was donor (male) metaphases. Cytogenetic and immunologic data in the latter patient were suggestive of relapse in donor cells.

Cytogenetic studies in an acute leukemia patient following cerebellar astrocytoma

Acute, monomyelogenous leukemia (AMML) was diagnosed in a patient with a derived 13;14 translocation and prior treatment for a cerebellar astrocytoma. A bone marrow aspirate at the time of diagnosis of leukemia showed abnormalities of chromosome 11, 12 and 16 in addition to the constitutional aberration. The patient's mother carried the same 13;14 translocation, as did 2 siblings, a maternal uncle, and four of his six children. The father had a reciprocal translocation between numbers 1 and 19 which was incidental to the present study.

CULTURED HUMAN CANCEROUS CELLS

This paper deals with two-year successive culture of human cancerous cells derived from squamous cell carcinoma of the maxillary sinus. The culture of the cells described in this paper has continued since June 4, 1975, and this cell line is considered to be stable and established. With a view to identifying the cultured cells, the author has been analyzing the cytologic findings by the seven major research tools which are detailed later.The patient was a 48-year-old man with well differentiated squamous cell carcinoma. In the maxillary sinus classified to T3N1M0. This patient underwent necrotomy twice, but died in October, 1976.1) In photomicroscopic study, most cultured cells were of sheetlike epithelial type which grew in multilayers and the superficial layer was cornified.2) Electron microscopic study showed that the cells possessed desmosomes and tonofilamentsand were of eqidermoid origin. 3) Chromosomal studies showed that the distribution of the number at the 5th and 25th generations fell in the hyperdiploid range. Karyotype analysis showed the presence of several chromosomes suffering constitutional aberration. These chromosomes served as the marker. 4) The plating efficiency was about 42% in a modification of Eagle's MEM, and about 20% even in 0.3% soft agar suspension. 5) The growth curve showed that a period of 6 days was required for the cells to attain a 4-to 5-fold count increase. 6) Five of six nude mice given the cultured cells successfully developed tumor. The tissue of this tumor was characterized by relatively clear cytoplasm and anisonucleotic nuclei, and proved to be identical with the cells that had been groan by the patient, on accountof the high nucleocytoplasmic ratio. 7) The dispersed cells of the successively cultured tumor were found to agglutinate even in low concanavalin A concentrations.These findings convinced the author that the successively cultured cells are derived from the epidermoid cells of human malignant tumor.

MEASURE OF METABOLIC SPEED IN CHILDREN

The basal metabolic rate, that is, the measure of the level of energy expenditure necessary to maintain basal metabolic processes, is the resultant of multitudinous and unceasing biochemical reactions; on these biochemical reactions depend the integrity of the body and the normal function of its cells. This so-called metabolic speed is innately controlled by the vegetative nervous system. Any constitutional aberration in basal metabolic behavior obviously provokes a disturbance in fundamental body phenomena. The clinical, the biologic and the social significance of such a disturbance will be considered in subsequent studies. As a prelude to our major study of constitutional dyscrasias in children, it was necessary to determine the most efficient laboratory procedure by which to measure, record and compare rates of basal metabolism. <h3>STANDARD METHODS OF DETERMINING METABOLIC SPEED</h3> Three well known methods serve in the estimation of metabolic speed: namely, the assessment of

A Review of the Recent Literature of Tar Cancer (1927–1931 Inclusive)

Introduction. The Chemistry of Tar. Pathological Anatomy of Tar Cancer. General Pathological Relationships. General Pathological Relationships. The Tar Tumor. Extracutaneous Tar Application and Extracutaneous Tar Tumors. Extraneous Factors Affecting the Development of Tar Tumors. Industrial Tar Cancer. Introduction The histological pleomorphism of malignant growths constitutes one of the strongest arguments against the theory that microorganisms or parasites are the specific etiological agencies in cancer. Indeed, the fact that our classification of tumors is so complicated, varied, and withal so unsatisfactory, constitutes a seemingly effectual bar against placing the cause of cancer at the door of any single agency, except perhaps that of constitutional aberration.